The invention relates generally to a method and device for measuring the concentration of target chemical analytes present in a biological system. More particularly, the invention relates to a method and device for predicting a future or past concentration of an analyte using a series of measurements obtained from a monitoring system. One important application of the invention involves predicting future or past blood glucose concentrations.
The generally accepted methods for time series forecasting are: extrapolation of linear regression, extrapolation of polynomial regression, autoregressive moving average (ARMA), and exponential smoothing as discussed by Diggle, Time Series: A Biostatistical Introduction, Oxford University Press, Oxford, (1990). Linear regression models are an acceptable means of forecasting, provided that the data being analyzed are linear. In the case where the data in question are nonlinear, polynomial regression is often used to model the data.
Autoregressive (ARMA) methods have been used with success in forecasting where the underlying phenomena are stationary (or can be converted to stationary), with superimposed fluctuations expressible as random white noise. These two requirements can be met for some physiologic variables, but plasma glucose levels in diabetic patients generally do not fit these requirements. The method of exponential smoothing is a special case of the ARMA method. The above methods forecast the future value of a variable based on the value of that variable at previous time points. Information on the first and second derivative of the variable with respect to time is not included. Inclusion of these time derivatives can substantially increase the accuracy of the forecasting method in the situation where the future value of a variable depends on its time rate of change.
The present invention provides a method and device for continually or continuously measuring the concentration of an analyte present in a biological system. The method entails continually or continuously detecting a raw signal from the biological system, wherein the raw signal is specifically related to the analyte. As the raw signals are obtained, a calibration step is performed to correlate raw signal with a measurement value indicative of the concentration of analyte present in the biological system. These steps of detection and calibration are used to obtain a series of measurement values at selected time intervals. In a preferred embodiment, the selected time intervals are evenly spaced. Once the series of measurement values is obtained, the method of the invention provides for the prediction of a measurement value at a further time interval which occurs either one time interval before, or one time interval after, the series of measurement values is obtained.
The raw signal can be obtained using any suitable sensing methodology including, for example, methods which rely on direct contact of a sensing apparatus with the biological system; methods which extract samples from the biological system by invasive, minimally invasive, and non-invasive sampling techniques, wherein the sensing apparatus is contacted with the extracted sample; methods which rely on indirect contact of a sensing apparatus with the biological system; and the like. In preferred embodiments of the invention, methods are used to extract samples from the biological sample using minimally invasive or non-invasive sampling techniques. The sensing apparatus used with any of the above-noted methods can employ any suitable sensing element to provide the raw signal including, but not limited to, physical, chemical, electrochemical, photochemical, spectrophotometric, polarimetric, colorimetric, radiometric, or like elements. In preferred embodiments of the invention, a biosensor is used which comprises an electrochemical sensing element.
In one particular embodiment of the invention, the raw signal is obtained using a transdermal sampling system that is placed in operative contact with a skin or mucosal surface of the biological system. The sampling system transdermally extracts the analyte from the biological system using any appropriate sampling technique, for example, iontophoresis. The transdermal sampling system is maintained in operative contact with the skin or mucosal surface of the biological system to provide for such continual or continuous analyte measurement.
The analyte can be any specific substance or component that one is desirous of detecting and/or measuring in a chemical, physical, enzymatic, or optical analysis. Such analytes include, but are not limited to, amino acids, enzyme substrates or products indicating a disease state or condition, other markers of disease states or conditions, drugs of abuse, therapeutic and/or pharmacologic agents, electrolytes, physiological analytes of interest (e.g., calcium, potassium, sodium, chloride, bicarbonate (CO2), glucose, urea (blood urea nitrogen), lactate, hematocrit, and hemoglobin), lipids, and the like. In preferred embodiments, the analyte is a physiological analyte of interest, for example glucose, or a chemical that has a physiological action, for example a drug or pharmacological agent.
A wide variety of mathematical techniques can be used to predict the measurement value at the further time interval (e.g., to predict unmeasured values at future or past time intervals). However, in a preferred embodiment of the invention, a Taylor Series Exponential Smoothing (TSES) function is used to predict measurement values. The TSES function is represented by the following equation:       y          n      +      1        =            y      n        +          α      ⁡              (                              y            n                    -                      y                          n              -              1                                      )              +                            α          2                2            ⁢              (                              y            n                    -                      2            ⁢                          y                              n                -                1                                              +                      y                          n              -              2                                      )            
wherein: xcex1 is an optimizable variable which is a real number of between 0 and 1 and is adjusted based on the particular measurements obtained and the relationship between those measurements and actual results; n is a time interval; and y is an analyte concentration or signal converted to an analyte concentration which signal measurement is optimized to fit the results sought e.g., to correspond with a reference analyte concentration.
Accordingly, it is an object of the invention to obtain a series of measurement values taken at selected time intervals, and then use the TSES function of the invention to predict a future measurement value occurring one time interval after the series is taken. In one particular aspect of the invention, the predicted future value is used to eliminate or substantially reduce a lag time inherent in a transdermal extraction sampling system.
It is also an object of the invention to obtain a series of measurement values taken at evenly spaced time intervals, and then use the TSES function of the invention to predict a past measurement value occurring one time interval prior to the time when the series is taken. In one particular aspect of the invention, the predicted past value is used in a calibration step to calibrate a sampling device.
It is a still further object of the invention to use the TSES function of the invention to predict future or past blood glucose values. In one aspect, the method of the invention is used in conjunction with an iontophoretic sampling device that provides continual or continuous blood glucose measurements. In another aspect of the invention, a predicted future value obtained using the subject TSES function is used to control an aspect of the biological system, particularly a physiological effect.
It is yet a further object of the invention to provide a method for measuring blood glucose in a subject. The method entails operatively contacting a glucose sensing apparatus with the subject to detect blood glucose and thus obtain a raw signal from the sensing apparatus. The raw signal is specifically related to the glucose, and is converted into a measurement value indicative of the subject""s blood glucose concentration using a calibration step. Further raw signals are obtained and converted into measurement values in order to obtain a series of measurement values at selected time intervals, and the series of measurements is then used to predict a glucose measurement value at a further time interval. In one aspect of the invention, the sensing apparatus is a near-IR spectrometer.
It is also an object of the invention to provide a monitoring system for continually or continuously measuring an analyte present in a biological system. The monitoring system is formed from the operative combination of a sampling means, a sensing means, and a microprocessor means which controls the sampling means and the sensing means. The sampling means is used to continually or continuously extract the analyte from the biological system across a skin or mucosal surface of said biological system. The sensing means is arranged in operative contact with the analyte extracted by the sampling means, such that the sensing means can obtain a raw signal from the extracted analyte which signal is specifically related to the analyte. The microprocessor means communicates with the sampling means and the sensing means, and is used to: (a) control the sampling means and the sensing means to obtain a series of raw signals at selected time intervals during a continual or continuous measurement period; (b) correlate the raw signals with measurement values indicative of the concentration of analyte present in the biological system; and (c) predict a measurement value at a further time interval which occurs either one time interval before or one time interval after the series of measurement values is obtained. In one aspect, the monitoring system uses an iontophoretic current to extract the analyte from the biological system.
It is a further object of the invention to provide a monitoring system for measuring blood glucose in a subject. The monitoring system is formed from an operative combination of a sensing means and a microprocessor means. The sensing means is adapted for operative contact with the subject or with a glucose-containing sample extracted from the subject, and is used to obtain a raw signal specifically related to blood glucose in the subject. The microprocessor means communicates with the sensing means, and is used to: (a) control the sensing means to obtain a series of raw signals (specifically related to blood glucose) at selected time intervals; (b) correlate the raw signals with measurement values indicative of the concentration of blood glucose present in the subject; and (c) predict a measurement value at a further time interval which occurs either one time interval before or one time interval after the series of measurement values is obtained. In one aspect, the monitoring system comprises a biosensor having an electrochemical sensing element. In another aspect, the monitoring system comprises a near-IR spectrometer.
In a further aspect, the methods and devices of the present invention can include enhancement of skin permeability by pricking the skin with micro-needles when the biological system includes skin, or, for example, a mucosal surface. Such pricking with micro-needles can facilitate extraction an analyte of interest from the biological system.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.